The present invention relates to compounds useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using said compounds of the present invention, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
Alzheimer""s disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3-xcex1-chloroimperialine as a highly selective M2 muscarinic antagonist.
The present invention is predicated on the discovery of a class of 1,4-di-substituted piperidines, some of which have M2 selectivity even higher than that of 3-xcex1-chloroimperialine. Logemann et al (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
In one aspect, the present application provides a compound having the general structure shown in Formula I: 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
Z is N, C(H), or C-(alkyl);
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94, or xe2x80x94C(S); 
R3 is 1 to 5 substituents which can be the same or different, each said substituent being either alkoxy or halo;
R4 is hydrogen or 1 to 3 substituents which can be the same or different, each said substituent being either alkyl or haloalkyl;
R27 is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, alkylthio, alkylthioalkylene, carboxyalkyl, imidazolyalkyl and indolyalkyl;
R28 is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, alkylthio, alkylthioalkylene, carboxyalkyl, imidazolyalkyl and indolyalkyl; or R27 and R28 can be joined together to form an alkylene group;
R29 is hydrogen, alkyl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, alkoxycarbonyl, aminocarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkylsulfonyl, arysulfonyl or xe2x80x94SO2xe2x80x94NHxe2x80x94R35;
R31 is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, aryl, cycloalkyl, hydroxyalkyl, aminoalkyl, hydroxy, xe2x80x94N(R35)2, xe2x80x94O-acyl, xe2x80x94N(R35)acyl, xe2x80x94OC(O)OR35 and xe2x80x94OC(O)N(R35)2;
R32 is hydrogen or 1 or 2 subsitutents which can be the same or different, each said substituent being independently selected from the group consisting of alkyl, aryl, cycloalkyl, hydroxyalkyl, aminoalkyl, hydroxy, xe2x80x94N(R35)2, xe2x80x94O-acyl, xe2x80x94N(R35)acyl, xe2x80x94OC(O)OR35 and xe2x80x94OC(O)N(R35)2, or R31 and R32 can be joined together to form the group xe2x80x94(CH2)rxe2x80x94, wherein r is 1, 2, 3, 4, 5 or 6;
R33 is aryl or heteroaryl with the proviso that when R33 is heteroaryl, the C(O)xe2x80x94R33 bond is to a carbon atom in the R33 group;
and
R35 is hydrogen, aryl or alkyl.
The compound of formula I can be useful as M2 muscarinic receptor antagonists and can be useful in the treatment of Alzheimer""s disease and other neurodegenerative or cognitive diseases. Another embodiment of this invention is directed to pharmaceutical compositions for the treatment of neurodegenerative or cognitive diseases. The compositions comprise a disease- or disorder-treating amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier therefor.